ClinVar Miner

Submissions for variant NM_000441.2(SLC26A4):c.84C>A (p.Ser28Arg)

gnomAD frequency: 0.00001  dbSNP: rs539699299
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169378 SCV000220764 likely pathogenic Pendred syndrome 2014-10-02 criteria provided, single submitter literature only
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000505875 SCV000605155 pathogenic not provided 2017-05-19 criteria provided, single submitter clinical testing The c.84C>A variant (rs539699299) has been observed as a homozygote (Park 2003) or in trans with a pathogenic variant (Ladsous 2014) in patients with a clinical diagnosis of Pendred syndrome (PS). It is listed in the Genome Aggregation Database (gnomAD) browser with an overall frequency of 0.003% (identified in 1 out of 30,956 chromosomes). Additionally, a different nucleic acid change leading to the same amino acid substitution (c.82A>C; p.Ser28Arg) a different variant in same codon (c.82A>G; p.Ser28Gly) have also been identified in patients with enlarged vestibular aqueduct (EVA; Park 2005 and Okamoto 2014, respectively). Analysis of the p.Ser28Arg variant in heterologous cell culture has revealed this substitution results in defects in ion flux compared to wild-type SLC26A4 protein (Dossena 2006a, Dossena 2006b, Yoon 2008). This variant is also listed in the ClinVar database as likely pathogenic (Variation ID: 188998). Therefore, the c.84C>A variant satisfies our criteria for classification as pathogenic.
Invitae RCV000505875 SCV000941761 pathogenic not provided 2023-08-29 criteria provided, single submitter clinical testing This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 28 of the SLC26A4 protein (p.Ser28Arg). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with Pendred syndrome (PMID: 11919333, 15679828, 16570074, 24224479, 29739340). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 188998). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SLC26A4 protein function. Experimental studies have shown that this missense change affects SLC26A4 function (PMID: 16791000, 18310264). For these reasons, this variant has been classified as Pathogenic.
Laboratory of Human Genetics, Institute of Biosciences - University of Sao Paulo RCV001580204 SCV001809838 pathogenic Autosomal recessive nonsyndromic hearing loss 4 criteria provided, single submitter research
Genome-Nilou Lab RCV001580204 SCV002027650 likely pathogenic Autosomal recessive nonsyndromic hearing loss 4 2021-09-05 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV000169378 SCV002027661 likely pathogenic Pendred syndrome 2021-09-05 criteria provided, single submitter clinical testing
Baylor Genetics RCV001580204 SCV004201856 pathogenic Autosomal recessive nonsyndromic hearing loss 4 2023-09-25 criteria provided, single submitter clinical testing
Natera, Inc. RCV000169378 SCV002079959 pathogenic Pendred syndrome 2021-02-12 no assertion criteria provided clinical testing

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